Substituted trioxo-octahydroanthracenes and octahydronaphthacenes



United States Patent Ofiice amass? atented Oct. 3, 1961 This inventionrelates to new organic compounds and more particularly is concerned withnovel substitrted trioxo-octahydroanthracenes which may be representedby the following general formula:

- O O (I) wherein R is hydrogen, halogen, hydroxy, lower alkyl, loweralkoxy, acyloxy or an aralkoxy radical, R is hydrogen, hydroxy, loweralkyl or a lower alkoxy radical, and R is hydrogen, cyano, carboxamidoor COOX wherein X is lower alkyl, mononuclear aryl or mononucleararalkyl and to novel tetracyclic compounds which may be representedby'the following general formula:

R Rs

A O to. til ad J) an wherein R is hydrogen or halogen, R is hydrogen,lower alkyl, acyl or mononuclear aralkyl, R is hydrogen or lower alkyland R is hydrogen, cyano or XCOOX wherein X is lower alkyl, mononucleararyl or mononuclear aralkyl. Suitable lower alkyl and lower alkoxygroups contemplated by the present invention are those having up toabout 6 carbon atoms. Suitable aralkoxy groups are benzyloxy,phenethoxy, etc. Suitable mononuclear aralkyl substituents are benzyl,phenethyl, phenylpropyl, phenylbutyl, etc. and suitable mononuclear arylsubstituents are exemplified by phenyl and substituted phenyl, suitablesubstituents on the phenyl ring being -Cl, Br, I, --NO and lower alkylradicals containing from 1 to 4 carbon atoms. Halogen is exemplified bychlorine and bromine.

The novel compounds are useful in the synthesis of polyoxygenated cycliccompounds such as, for example, certain tetracyclic esters. In addition,the new compounds are particularly effective as chelating, complexing orsequestering agents for polyvalent metallic ions. The complexes formedwith polyvalent metallic ions are particularly stable and usually squitesoluble in various organic solvents. This, of course, makes them usefulfor a variety of purposes such as in biological experimentation wherethe removal of traces of polyvalent metallic ions may be of greatimportance. They are also useful in analyses for polyvalent metallicions which may be complexed and. extracted by means of these reagents.Other uses common. to sequestering agents are also apparent for thesecompounds.

The new compounds represented by (I) above may be prepared by a seriesof reactions starting with the tetrahydro-4-oxo-2-naphthaleneaceticacids described and claimed in the copending application of Raymond G.Wilkinson et al., Serial No. 748,613, filed July 15, 1958, nowabandoned. In accordance with the present invention, thetetrahydronaphthalene-Z-acetic acid is first converted to thecorresponding acyl halide by treatment with a suitable agent such asoxalyl chloride, or alternatively, by using a mixed carboxylic-carbonicanhydride derivative. Diethyl malonate is then acylated and theresultant r acyl malonate cyclized to the octahydroanthracene. The

octahydroanthracene can be treated to remove the carbethoxy group or canbe converted to Z-carboxa'mido octahydroanthracene by first treatingwith alcoholic am monia at 70110 in a sealed vessel followed by strongacid hydrolysis.

In order to prepare the novel tetracyclic compounds represented byFormula II above, the tetrahydronaphthaleneacetic acid is firstconverted to the corresponding acyl halide by treatment with an agentsuch as oxalyl chloride. The intermediate acyl halide so formed is thenconverted to the desired naphthaleneacetaldehyde by a suitable reductionprocess. The aldehyde so formed is then treated with cyanoacetarnide toform the corresponding dicyano glutaramide, which product is hydrolyzedin hydrochloric acid in the conventional manner. The glutaric acid isthen subjected to a two-step methylation and the resulting product istreated with sodium hydride to form the correspondingoctahydroanthracene acetate. This product is then brominated to form theappropriate gromoketone which is treated with boiling collidine to formthe corresponding naphthol. This latter product is methylated withpotassium carbonate and dimethyl sulfate. The tricyclic acid is obtainedby alkaline hydrolysis and is then treated with oxalyl chloride, oralternatively with ethyl chloroformate and then with malonic ester andfinally with sodium hydride to form the desired tetracycline ester. Theconditions leading to the formation of product (H) are detailed in theexamples which follow.

EXAMPLE 1 Preparation of diethyl 8-chlor0-5-m'ethoxy-4-0x0-1,2,3,4-letrahydronaphthalene-Z-acetyl malonate Following the procedure of theaforesaid copending application Serial No. 748,613, Z-chloro-S-methoxytoluene is brominated to the corresponding .benzyl bromide. Theresulting compound is treated with diethyl malonate and the benzylmalonic ester so formed is reduced with lithium aluminum hydride in aconventional manner to form the corresponding propanediol. Thebis-methane sulfonate is then formed with methanesulfonylchloride andthe resulting compound is converted to the corresponding dinitrile byreaction with an alkali metal cyanide. The dinitrile is hydrolyzed tothe corresponding benzyl glutaric acid in a refluxing solution of base.The glutaric acid is then converted to the corresponding.naplhthaleneacetic acid by treatment with polyphosphoricacr To asolution of 270 milligrams (0.001 mole) of the so-prepared 8chloro-5-methoxy-4-oxo-1,2,3,4-tetrahydronaphthalene-Z-acetic acid in 15cc. of dry tetrahydrofuran is added 101 milligrams (0.14 cc., 0.001mole) of triethylamine and the solution is then cooled in anice-alcoholbath to 10 to 12. To the reaction is added 108.5 milligrams (0.095 cc.,0.001 mole) of ethyl chloroformate, and then 0.001 mole of diethylmagnesiomalonate dissolved in 20 cc. of dry ether. The reaction is nowallowed to stand at room temperature for two days and is then evaporatedto dryness in vacuo and the residue taken up in 20 cc. of ether and 20cc. of 0.05.

both layers are poured off and the solid is collected on a filter. Afterwashing with water and ether and drying, the solid weights 270milligrams. A suspension of 150 milligrams of this product in 3 cc. ofwater is heated on the steam bath and methanol is added slowly untilnearly all is in solution (about 7 cc. of methanol). After filtering andcooling, a blue crystalline solid is deposited slowly. This product isfiltered oflF, washed well and dried at 60 for 6 hours in vacuo; weight,90 milligrams; M.P. shrinks and slowly melts at 77-100.

Analysis.Calculated for C H O Cl Cu: Cl, 8.06; 01, 7.25; OCH 21.2.Found: Cl, 8.19; Cu, 7.27; OCH 22.10.

EXAMPLE 2 Preparation of diethyl5-acetoxy-8-chloro-1,2,3,4-tetrahydr-4-0xo-2-naphthylacetyl malonateFollowing the procedure of theaforesaid copending application,-acetoxy-8-chloro-1,2,3,4-tetrahydro-4-oxo- 2-naphthalene acetic acid isprepared from 8-chloro-5- methoxy 4oxo-l,2,3,4-tetrahydronaphthalene-2-acetic acid by acid cleavage of themethyl ether followed by acetylation with acetic anhydride.

. 297 milligrams (0.001 mole) of the so-prepared 5- acetoxy 8 chloro1,2,3,4-tetrahydro-4-oxo-2-naphthalane-acetic acid is dissolved in 15milliliters of chloroform and the solution is cooled in an ice-ethanolbath to -12 and triethylamine (0.14 milliter, 0.001 mole) is added.Ethyl chloroformate (0.1 milliliter, 0.001 mole) is added to the clearsolution and allowed to stir at -l2 for ten minutes. Diethylmagnesiomalonate (0.001 mole in 15 milliliters ether) is added, the icebath removed and the mixture stirred overnight at room temperature. Thereaction mixture is then concentrated to dryness in vacuo, the residuetaken up in 25 milliliters of ether and shaken mechanically with 15milliliters of 0.3 N HCl for 1 hour. The ethereal layer is separated,washed twice with milliliter portions of water, and then shaken withmilliliters of copper acetate solution. A blue solid forms slowly and iscollected on a filter after 8 hours. Yield of copper salt of diethyl 5-acetoxy 8 chloro-1,2,3,4-tetrahydro-4-oxo-2-naphthylacetyl malonate, 160milligrams. A small quantity is recrystallized from a toluene-hexanemixture for analysis; M.P. 180 to 198.

Analysis.Calculated for C H ClO Cut: C, 52.64; H, 4.76; Cl, 7.58; Cu,6.80. Found. C, 53.81; H, 5.02; Cl, 7.60; Cu, 7.27, 7.38, 7.00.

EXAMPLE 3 Preparation of diethyl5-benzyloxy-8-chl0ro-],2,3,4-tetrahydr0-4-0x0-2-naphthylacetyl malonateFollowing the procedure of the aforesaid copending application, 5benzyloxy-8-chloro-l,2,3,4-tetrahydro-4- oxo-2-naphthaleneacetic acid isprepared from 8-chloro- 5methoxy-4oxo-1,2,3,4-tetrahydronaphthalene-2-acetic acid by acidcleavage of the methyl ether followed by benzylation with benzylchloride.

329 milligrams (0.00095 mole) of the so-prepared 5- benzyloxy 8 chloro1,2,3,4-tetrahydro-4-oxo-2-naphthaleneacetic acid is slurried in 25milliliters of chloroform and the suspension is cooled in an ice-ethanolbath to l2, and triethylamine (0.14 milliliter, 0.001 mole) is added.Ethyl chloroformate (0.1 milliliter, 0.001 mole) is added to theresultant clear solution and allowed to stir at 12 for ten minutes.Diethyl magnesiomalonate (0.001 mole in 5 milliliters of toluene) isthen added, the ice bath removed and the mixture stirred overnight atroom temperature. The reaction mixture is then concentrated to drynessin vacuo, the residue taken up in 25 milliliters of ether and shakenmechanically with 15 milliliters of 0.3 N HCl for one hour. The ethereallayer is separated, Washed twice with 10 milliliter portions of water,and then shaken mechanically With 15 milliliters of copper acetatesolution. A blue solid forms slowly and is collected on a filter after14 hours. The impure copper derivative is recrystallized from achloroform-hexane mixture to yield 220 milligrams of pure copper salt ofdiethyl S-benzyloxy-S-chloro-l,2,3,4-tetrahydro-4-oxo-2 naphthylacetylmalonate, M.P. 175-8".

Analysis.--Calculated for C H ClO Cu C, 60.31; H, 506; Cl, 6.85; Cu,6.14. Found: C, 60.20; H, 5.09; Cl, 7.27; Cu, 6.07.

EXAMPLE 4 Preparation of Z-carbethoxy-S-chl0ro-8-meth0xy-1,3,9-trioxo-I,2,3,4,4a,9,9a,1 O-octahydroanthracene 8 chloro 5 methoxy 4 oxo 1,2,3,4tetrahydro naphthalene-Z-acetic acid (10.8 grams, 0.040 mole), preparedfollowing the procedure outlined in Example 1, is suspended in 50milliliters of sodium dried benzene. The suspension is refluxed and asolution of oxalyl chloride (6.42 milliliters, 0.080 mole) in 50milliliters of sodium dried benzene is added dropwise over a thirtyminute period. A clear yellow solution forms as the reaction proceeds.The solution is refluxed an additional thirty minutes and then theexcess oxalyl chloride and benzene are removed under reduced pressure.The oily residue is dissolved in 25 milliliters of benzene and againconcen trated to an oil under reduced pressure. The oily acid chlorideis dissolved in 100 milliliters of sodium dried toluene.

The magnesium salt of diethyl malonate is prepared by heating magnesiummetal (972.8 milligrams, 0.040 mole), carbon tetrachloride (0.3milliliter), absolute ethanol (7.28 milliliters) and diethyl malonate(6.08 milliliters, 0.40 mole) intermittently on a steam bath for fifteenminutes, then 100 milliliters of sodium dried ether is added andrefluxed with stirring until all of the magnesium is dissolved(approximately two hours). The ethereal solution of magnesiomalonicester is cooled to room temperature and the toluene solution of the acidchloride prepared above is added dropwise, with stirring,

over a thirty minute period. After seven minutes sodium chloride beginsprecipitating. After ten minutes the magnesium salt of the acylatedmalo-nic ester begins separating as a yellow gum. The reaction mixtureis refluxed for twenty minutes after the addition of the acid chloride,is cooled to room temperature and sodium hydride added (4.0 grams, 0.160mole). An additional 200 milliliters of sodium dried toluene is addedand the ether removed by distillation. The reaction mixture is thenrefluxed for seventeen hours. The dark brown suspension is cooled toroom temperature and 10 milliliters of absolute ethanol added todecompose the excess sodium hydride. The reaction mixture ismechanically shaken for one hour with 200 milliliters of 1 N HCl, thetoluene layer separated, washed twice with water, dried over anhydrousmagnesium sulfate and filtered. The filtrate is concentrated underreduced pressure to a syrupy residue and 50 milliliters of absoluteethanol added. The mixture is heated on a steam bath and allowed toslowly cool to room temperature. Brownish yellow crystals of crudecyclized product are deposited. Yield 4.97 grams (34%), M.P. 159-64.4.68 grams of the crude are recrystallized from 200 milliliters ofabsolute ethanol and 20 milliliters of dimethylformamide, yielding 3.72grams of the pure octahydroanthracene (26.7%), M.P. 1647.

Analysis.Calculated for C H 'ClO C, 59.26; H, 4.70; Cl, 9.72. Found: C,59.39; H, 4.69; Cl, 9.76.

EXAMPLE 5 Preparation of ethyl 8-benzyi0xy-5-chl0r0-I,2,3,4,4a,9,9a, 1O-octahydro-I ,3,9-lri0x0-2-nnthr0ate 5 benzyloxy 8 chloro 1,2,3,4tetrahydro 4 oxo-2-naphthaleneacetic acid (1.3 grams, 0.004 mole),prepared following the procedure outlined in Example 3, is slurried in40 milliliters of toluene. The suspension is cooled in an ice-ethanolbath to -12 and triethylamine (0.56 milliliter, 0.004 mole) added. Ethylchloroformate (0.38 milliliter, 0.004 mole) is added to the clearsolution and allowed to stir at --12 for ten minutes. Diethylmagnesiomalonate (0.004 mole in 20 milliliters of toluene) is added, theice bath removed and the mixture is stirred at room temperature forthree hours. The reaction mixture is then washed with 20 milliliters of1 N N01 and three 15 milliliter portions of water. The toluene layer isdried over anhydrous magnesium sulfate, liltered and azeotropicallydistilled to remove any residual water. Sodium hydride (386 milligrams,0.016 mole) is added to the thoroughly dried toluene solution and themixture refluxed for 1.5 hours, during which time a dark brown colordevelops. The reaction is then cooled, 5 milliliters of ethanol added todecompose any residual sodium hydride and shaken With 20 milliliters of6 N HCl. The aqueous layer is extracted with three ten milliliterportions of toluene and the combined toluene layers Washed thrice with15 milliliter portions of water, dried over anhydrous magnesium sulfateand concentrated to a dark brown oil in vacuo. Upon the addition of 10milliliters of ether, light yellow crystals are deposited. The crystalsare collected on a filter, washed thoroughly with several portions ofether and air dried. Yield of ethyl 8 benzyloxy 5 chlorol,2,3,4,4a,9,9a,10 octahydro l,3,9 trioxo-2-antl1roate, 640 milligrams(36.2%), M.P. 149-52. Recrystallization of a small amount from ethanolraises the M.P. to 150-52.

Analysis.-Calculated for C H ClO C, 65.5; H, 4.80; Cl, 8.06. Found: C,65.72; H, 5.08; Cl, 8.23.

EXAMPLE 6 Preparation of ethyl5-chl0ro-1,2,3,4,4a,9,9a,10-0ctahydr-8-hydr0xy-1,3,9-tri0x0-2-anthroateA solution of ethyl 8-benzyloxy-5-chloro-1,2,3,4,4a,9,9a,IO-Octahydro-1,3,9-trioxo-2-anthroate (220 milligrams, 0.0005 mole)in 20 milliliters of methyl Cellosolve is added to a suspension ofpre-reduced platinum oxide (22 milligrams) in 25 milliliters of methylCellosolve and 1 drop of glacial acetic acid is added. The mixture isreduced with hydrogen at atmospheric pressure. After 2.5 hours twoequivalents of hydrogen are absorbed and the reaction slows appreciably.The catalyst is removed by filtration and the solution concentrated todryness in vacuo. The crude product is recrystallized from 7 millilitersof ethanol. Yield of pure ethyl chloro-1 ,2,3,4,4a, 9,921, l0-octahydro-8-hydroxy- 1,3,9-trioxo-2-anthro ate, 1 15 milligrams (72.7%bright yellow crystals, M.P. 142-4".

Analysis.-Calculated for C17H15O Cl: C, 58.2; H, 4.31; CI, 10.13. Found:C, 58.54; H, 4.67; CI, 10.12.

EXAMPLE 7 Preparation of 5-chlor0-8meth0xy-1,3,9-tri0xo-1,2,3,4,4a,9,9a,1 O-octahydroanthracene 2 carbethoxy 5 chloro 8 methoxy 1,3,9trioxol,2,3,4,4a,9,9a,IO-Octahydroanthracene (900 milligrams, 0.0025mole), preparedin Example 4, is dissolved in 50 milliliters of 1 Nsodium hydroxide. The solution is heated on a steam bath for six hoursin an. atmosphere of nitrogen. The reaction mixture is then cooled andacidified to pH 1 with 4 N hydrochloric acid. The yellow crystals whichprecipitate are collected on a filter and dried in a vacuum desiccatorover P 0 Yield of crude product 615 milligrams (88.6%).Recrystallization of 100 milligrams from 2 milliliters of 95% ethanolgives 40 milligrams of pure 5-chloro-8-methoxy-1,3,9-trioxo-l,2,3,4,4a,9,9a,10-octahydroauthracene, M.P. 168-73 with dec.

Analysis.--Calculated for C H O Cl: C, 61.55; H, 4.48; Cl, 12.11. Found:C, 61.55; H, 4.69; CI, 12.03.

EXAMPLE 8 Preparation of 2-carboxamido-5-chl0r0-8-methoxy-I,3,9-trioxo-l ,2,3,4,4a,9,9a,10-Octahydmwnthracene A suspension of2-carbethoxy-S-chloroB-methoxy-1,3,

9 trioxo 1,2,3,4,4a,9,9a,10 octahydroanthracene (1.0 gram, 0.00276 mole)in 25 milliliters of absolute methanol contained in a stainless steelbomb is cooled to 0 and saturated with anhydrous ammonia. The bomb issealed, heated at for five hours and then allowed to stand at roomtemperature overnight. The methanol is evaporated oil under an air jetat room temperature and the residue slurried in 10 milliliters of 1 NNaOH. The tan solid is collected on a filter and then heated in 10milliliters of ethanol. The insoluble portion is collected on a filterand dried in vacuo over P 0 to yield 350 milligrams of crude product.150 milligrams of this material is heated on a steam bath for tenminutes with 15 milliliters of 4 N HCl. The yellow crystals arecollected and recrystallized from a dimethylformamide-water mixture,yielding 65 milligrams of Z-oarboxamido-S- chloro-8-methoxy-3-('or 1- or9-)imino-1,9-dioxo-1,2,3,4, 4a,9,9a,10-octahydroanthracene, M.P. 194-197with dec. Crude 2-carboxamido-S-chloro-S-methoxy-3-(or 1- or 9 )imino1,9 dioxo 1,2,3,4,4a,9,9a,10 octahydroanthracene milligrams) is heatedon a steam bath with 5 milliliters of 4 N HCl for three hours and thenallowed to stand at room temperature for an additional three hours. Thereaction mixture is filtered and the crude amide recrystallized from adimethylformamideethanol mixture, yielding 55 milligrams of pure2-carb0xamido 5 chloro 8 methoxy 1,3,9- trioxo 1,2,3,4,4a,9,9a,lO-octahydroanthracene, M.P. 239-241 dec.

Analysis-Calculated for C H NClO C, 57.24; H, 4.20; N, 4.17; CI, 10.56.Found: C, 57.32; H, 4.54; N,

EXAMPLE 9 Preparation of 5-chlor0-1,2,3,4,4a,9,9a,10-0ctahfydr0-8-hydroxy-I,3,9-tri0x0-2-anthmmide 5 ch-loro 1,2,3,4,4a,9,9a,10 octahydro8 methoxy- 1,3,9-tr1'oxo-2-anthramide (460 milligrams, 0.00137 mole), isslurried in 25 milliliters of anhydrous 30% HBr in glacial acetic acid.The reaction mixture is refluxed for 1.5 hours and the solutionconcentrated to dry ness in vacuo. The residual dark green solid iswashed with water until the washings give a negative silver nitratetest. The crude demethylated product (400 milligrams) is dissolved withthe aid of heat in 40 milliliters of methyl Cellosolve, treated withdecolorizing carbon and filtered. The filtrate is concentrated to 25milliliters and 10 drops of water added. Upon cooling light yellowcrystals precipitate, are collected on a filter and dried in vacuo at100. Yield of 5-chloro-1,2,3,4,4a,9,9a,10 octahydro-8-hydroxy-1,3,9-trioxo-2-anthramide, 180 milligrams M.P. 230-3 Uponstanding overnight at 5 the filtrate yields an additional 54 milligramsof the demethyla'ted compound. Total yield 234 milligrams (53%).

AnaZysis.-Calculated for C H O5ClN: C, 56.0; H, 3.77; Cl, 11.05; N,4.36. Found: C, 56.29; H, 4.08; Cl,

EXAMPLE 10 Preparation of2,2-dicyano-3-(8-chl0r0-],2,3,4-tetrahydro-5-methoxy-4-0x0-2-naphthylmethylglutaramide)Cyanoacetamide (8.0 grams, .095 mole) and 8-ch1oro- 1,2,3,'4 tetrahydro5 methoxy 4 oxo 2 naphthaleneacetaldehyde, prepared by reduction of thecorresponding naphthaleneacetyl chloride described in Example 4, aredissolved in absolute ethanol (300 milliliters) with the aid of heat.The solution is cooled, filtered, five rops of pipen'dine added and theliquid is allowed to stand at room temperature for 24 hours. The whitecrystals (11.7 grams, 92%) which deposit are collected by suctionfiltration, washed with ether, and air-dried. This highly insolubleproduct has a-melting point of -155, but the melting point of otherbatches run in "a similar manner varies from 105 to despite constantanalyses. The sample is dried for analysis at 60 for 3 hours in vacuo.

Analysis-Calculated for C H O N Cl-C 'H O: C,

56.2; H, 5.62; N, 12.49; Cl, 7.92. Found: C, 55.61; H, 5.62; N, 12.54;Cl, 8.40.

EXAMPLE 11 Preparation of 3-(8-chl0ro-1,2,3,4-tetrahydro-5-hydroxy-4-oxo-2-naphthylmethyl)-glutaric acid 2,2 dicyano 3 (8 chloro 1,2,3,4tetrahydro 5- methoxy 4 oxo 2 naphthylmethyl) glutaramide (10.0 grams,0.0249 mole) is slurried in a mixture of concentrated hydrochloric acid(405 milliliters) and glacial acetic acid 135 milliliters) Uponrefluxing a clear yellow solution forms which gradually turns bright redthen brown. After twelve hours the reaction is cooled and filtered. Thefiltrate is concentrated in vacuo to approximately twothirds volume. Thelight yellow crystals which separate are collected on a filter, washedthoroughly with water and dried in vacuo over phosphorous pentoxide andpotassium hydroxide pellets. Yield of the glutaric acid is 5.9 grams(70%), M.P. 177-80. Recrystallization from ethyl acetate raises themelting point to 1815-182".

Analysis.Calculated for C1 H1qClO5: C, 56.4; H, 5.03; Cl, 10.42. Found:C, 56.45; H, 5.30; Cl, 10.36.

EXAMPLE 12 Preparation of3-(5-benzyloxy-8-chloro-1,2,3,4-tetrahydro-4-0xo-2-naphthylm'ethyl)glutaric acid 3 (8 chloro 1,2,3,4 tetrahydro 5 hydroxy 4-oxo-naphthylmethyl)glutaric acid (0.920 gram, 0.0027 mole) is dissolvedin 25 milliliters of 1 N sodium hydroxide. Benzyl chloride (1.8 grams,0.0142 mole) is added and the mixture refluxed for two hours undernitrogen. The reaction is cooled and extracted with five milliliterportions of ether. The aqueous layer is separated, acidified and the tanoily solid which separates is extracted into ethyl acetate. The organiclayer is dried over anhydrous magnesium sulfate, filtered andconcentrated to a light tan solid in vacuo. Crude 3-(5-benzyloxy- 8chloro 1,2,3,4 tetrahydro -4 oxo naphthylmethyl)- glutaric acid 1.1gram) is obtained.

An analytical sample is obtained from ethyl acetate as a colorlessmicrocrystalline solid, M.P. l74176.

Analysis.Calculated for C H O Cl: C, 64.2; H, 5.38; Cl, 8.25. Found: C,64.68; H, 6.17; Cl, 8.22.

EXAMPLE 13 Preparation of dimethyl 3-(5-benzyl0xy-8-chloro-I,2,3,4-tetrahydro-4-0xo-2-naphthylmethyl glutarate Crude3-(5-benzyloxy-8-chloro-1,2,3,4-tetrahydro-4-oxo-Z-naphthylmethyl)glutaric acid (1.1 gram, 0.0024 mole) is dissolved in50 milliliters of methanol and 1 drop of concentrated sulfuric acid isadded. The solution is refluxed on a steam bath for 2 hours,concentrated in vacuo to approximately 8 milliliters and diluted with 50milliliters of ethyl acetate. The ethyl acetate solution is washedthrice with 20 milliliter portions of 1 N sodium bicarbonate and thricewith 20 milliliter portions of water. The organic layer is dried overanhydrous magnesium sulfate, filtered and concentrated to an oilyresidue in vacuo. Yield of crude dimethyl 3-(5-benzyloxy-8-chloro-1,2,3,4-tetrahydro-4-oxo-naphthylmethyl)glutarate is 1.0 gram.

Recrystallization of crude diester from ether-petroleumether produces ananalytical sample, colorless crystals, M.P. 6263.

Analysis.--Calculated for C H O Cl: C, 65.43; H, 5.93. Found: C, 65.10;H, 6.04.

EXAMPLE 14 Preparation of methyl 5-benzyloxy-8-chloro-1,2,3,4,4a,9,9a,10-0ctahydro-4,10-dioxo-Z-anthraceneacetate Dimethyl3-(5-benzyloxy-8-chloro-1,2,3,4-tetrahydro-4- oxo-naphthylmethyl)glutarate (1.73 grams, 0.0037 mole) is dissolved in 100 milliliters oftoluene. Sodium hydride (230 milligrams, 0.010 mole) is added and themixture refluxed under nitrogen for 4.5 hours, cooled to roomtemperature and allowed to stand overnight. Additional sodium hydride(150 milligrams, 0.0063 mole) is added and the reaction is refluxed 1.5hours. The excess hydride is decomposed by the addition of 2 millilitersof methanol. The solution is diluted with 50 milliliters of chloroform,washed twice with 25 milliliter portions of 1 N hydrochloric acid andtwice with 25 milliliter portions of water. The organic layer isseparated, dried over anhydrous magnesium sulfate, filtered andconcentrated to an oily residue in vacuo. The residue is dissolved in 50milliliters of ether and 80 milliliters of hexane added. Upon standingat 5 overnight small white crystals are deposited. The yield ofmethyl-S-benzyloxy-8-chloro- 1,2,3,4,4a,9,9a,10 octahydro 4,10 dioxo 2anthracene-acetate is 495 milligrams, M.P. -105. Work-up of the filtrateyields an additional 200 milligrams of the desired product. Total yieldof crystalline material is 44 of theory. Repeated recrystallization ofcrude product from ether raises the M.P. to 117-121".

Analysis-Calculated for C H CIO C, 67.5; H, 5.41; Cl, 8.31. Found, C,67.47; H, 5.58; Cl, 8.85.

EXAMPLE 15 Preparation of methyl S-benzyloxy-I0-hydroxy-8-chlaro- I,2,3,4-tetrahydro-4-0x0-2-anthraceneacetate Crystalline methyl5-benzyloxy-8-chloro-1,2,3,4,4a,9,9a,10-octahydro-4,10-dioxo-2-anthraceneacetate (6.5 grams) is dissolved ina mixture of ethyl acetate (40 milliliters) and glacial acetic acid (80milliliters). Anhydrous sodium acetate power (1.75 grams) is added andthe mixture stirred magnetically until a solution is obtained.

, The reaction vessel is cooled to 0-5 and to the contents are slowlyadded, with stirring, 16 milliliters of a 1M solution of bromine inglacial acetic acid. After addition of the bromine solution, an aliquotof the reaction possesses an ultraviolet absorption ratio (6 360/6 335)of 0.55 in 0.1 N alkali. The entire reaction mixture is poured intobenzene, the benzene solution washed with salt solution containing alittle sodium sulfite, then with four successive portions of water. Thebenzene layer is dried over magnesium sulfate and the solvent removed togive the crude bromoketone (7.0 grams) as a pale pink foam.

The bromoketone is dissolved in 45 milliliters freshly distilledcollidine and the solution heated under nitrogen at reflux for 12minutes. The cooled supernatant is separated from solid collidinehydrobromide by decantation, the solid washed with ether-benzene and theether and collidine solutions combined. The extracts are washed withice-cold 3 N sulfuric acid until the collodine odor is no longerpresent. The organic extracts are dried over magnesium sulfate and thesolvent evaporated in vacuo. There remain 5.5 grams (84%) of methylS-benzyloxyl0-hydroxy 8 chloro 1,2,3,4 tetrahydro 4 oxo 2-anthraceneacetate. The analytical sample is obtained from ether, M.P.132-134".

Analysis.--Calculated for C H O Cl: C, 67.84; H, 4.98. Found: C, 67.45;H, 5.47.

EXAMPLE 16 Preparation of methyl S-benzyloxy-I0-meth0xy-8-chl0r0-1,2,3,4-tetrahydr0-4-oxo-2-anthraceneacetate To a solution of theproduct of Example 15 and dimethyl sulfate (3.2 milliliters) inanhydrous toluene (160 milliliters) is added micronized anhydrouspotassium carbonate (33 grams, previously dried 12 hours at and thestirred suspension held at reflux for six hours. The cooled mixture isfiltered through a sintered-glass suction funnel and the filter cake (K00 washed with benzene. The combined filtrates are reduced to 30milliliters in vacuo and chromatographed over 100 grams of alumina.Eluates corresponding to (A) benzene to benfiche-10% ethyl acetate andB) benzene-25% ethyl acetate to benzene-50% ethyl acetate are"separately collected. Concentration and 'recrystallizationof theresidues from ether gives from "('A') 0.80 gram of yellow needles, M.P.129-130; from- (B) 1.24 grams tan needles, M.P. l27-l28; mixed M.P.127-1285 The analytical sample is prepared from '(B) byrecrystallization from ether and drying in vacuo at 65.

Analysis.-Calculated for C H O Cl; C, 68.36; H, 5.29; OCH 14.1. Found:C, 68.49; H, 5.86; OCH 14.65.

EXAMPLE 17 Preparation 07 5-benzylbxy-10-methotry-Xwidow-1,25,4-Ietmhydro-4-ox0-2-anthracene acetic acid A solution of 2.5 gramspotassium hydroxide, 4 milliliters water and 35 milliliters methanol isbrought to reflux and allowed to cool in a nitrogen atmosphere. To thecold solution is added the product of Example 16 1.17 grams), and thesuspension brought to reflux under nitrogen. After one hour of re'fiuxthe solution is evaporated in vacuo to approximately one half theoriginal volume. The reaction mixture is poured into excess icecold 1 Nsulfuric acid and the organic product extracted into ethyl acetate. Theethyl acetate is washed twice with water and dried over magnesiumsulfate. Evaporation of solvent gives 1.09 (96%) of crystallinetricyclic acid, tan needles melting at 169-171.

The analytical sample is recrystallized three times from ethyl acetateto give straw-colored needles, M.P. 175-176". Solvent of crystallizationis removed by drying at 100 in vacuum for four hours.

AnaIysis.--Calculated for C H O Cl: C, 67.81; H, 4.96; OCH 7.31. Found:C, 67.72; H, 5.06; OCH 7.27.

EXAMPLE 18 Preparation of ethyl -benzyloxy-7-chloro-1I-methoxy- 1,3,]2trioxo 1,2,3,4,4a,5,12,12a ocrahydronaphthacene-Z-carboxylate 1 Asuspension of 1.01 grams (2.3 millimoles) of recrystallized tricyclicacid prepared in Example 17 in 50 milliliters of anhydrous toluene isstirred magnetically at room temperature under a dry nitrogenatmosphere. Addition of triethylamine (0.38 milliliter, 2.75 millimoles)effects solution of the acid. The mixture is cooled to 10 and ethylchloroformate (0.26 milliliter, 2.75 millimoles) is added. The stirringat -10 under nitrogen is maintained for minutes, at which time there isadded 5.5 milliliters of 0.45 magnesio ethoxy'diethyl malonate intoluene. The reaction mixture is allowed to stand at room temperaturefor 18 hours; it is then poured into excess cold 2 N sulfuric acid. Theacyl malonate is extracted into benzene, the benzene extracts washedwith sodium bicarbonate and water, dried over magnesium sulfate, andevaporated to leave 1.39 grams of product. The crude acyl malonate is ayellow gum having infrared maxima at 5.75-5.80p. and 5.94 andultraviolet spectrum identical with that of the starting acid.

The acyl malonate (1.39 grams) is dissolved in 20 milliliters of tolueneand evaporated to dryness in vacuo, then held at 95 at 1 mm. vacuum forone hour. The dried acyl malonate is dissolved in 35 milliliterssodiumdried reagent toluene. To the solution is added sodium hydride inoil (1.20 grams of a solid suspension ca. 52% NaH by weight) and thestirred mixture refluxed under a nitrogen atmosphere for twenty minutes.

The reaction mixture, which turns from the original very pale yellow toa strong golden-brown color, is cooled to room temperature and thencooled further in ice-water. The remaining sodium hydride is destroyedby the cantious dropwise addition of glacial acetic acid (3 milliliters)followed by the very slow addition of absolute ethanol. The resultingsolution is poured into cold disponges m ssianic acid, are organiccomposers xtracted into ethyl acetate, aind the extracts. washed withsodium bicarbonate and water. After dryingfover magnesium sul' f'ate thesolvent is evaporated to leave an oil (which contains ca. .016 grainmineral 'oil from the NaI-I suspension) The oil is taken up in 35milliliters dry 'ether and the solution scratched until crystallizationcommences. On standing of the solution in the icebox overnight there isobtained 415 milligrams (35%) of golden yellow crystals, M.P. 170-171".v

The analytical sample is recrystallized from ethyl acetate anddried atfor four hours in vacuum; golden needles, M.P. 169-171". H

Analysis.Calculate d for C H Q' 'C1: C, 66.88; H, 4.84; OCH 11.90.Found: C, 66.85; H, 5.08; OCH 11.11.

We claim: 1. A compound of the formula:

wherein R is selected from the group consisting of chlorine and bromine,R is a member of the group consisting of hydrogen, lower alkyl, andphenyl lower alkyl radicals, and R is a member of the group consistingof hydrogen, carboxamido, and lower carbalkoxy radicals.

2. A compound of the formula:

\I/ I I ConRa OR; OR; o 0 wherein R is selected from the groupconsisting of chlorine and bromine, R is lower alkyl, and R is a memberof the group consisting of hydrogen, lower alkyl, and phenyl lower alkylradicals.

3. The method of preparing a compound of the formula:

wherein R is selected from the group consisting of chlorine and bromine,R is lower alkyl, and R is a member of the group consisting of hydrogen,lower alkyl, and phenyl lower alkyl radicals which comprises treating a4-oxo-1,2,3 ,4 tetrahydro 2 naphthaleneacetyl chloride with adi(lower)alkyl magnesiomalonate to form the corresponding acyl malonicester and cyclizing said ester with sodium hydride to form thecorresponding 1,3,9- trioxo l,2,3,4,4a,9,9a,10 octahydroanthracene 2carboxylate.

4. The method of preparing a compound of the formula:

COgRa wherein R is selected from the group consisting of chlorine andbromine, R is lower alkyl, and R is a member of the group consisting ofhydrogen, lower alkyl, and

11 12 phenyl lower alkyl radicals which comprises treating a 10. 5-ch1oro-1,2,3,4,4a,9,9a,10-octahydro 8 hy-4-oXo-1,2,3,4-tetrahydro-2-anthraceneacetyl chloride withdroxy-1,3,9-trioxo-2-anthramide. a di(1ower)alky1 magnesiomalonate toform the corre- 111. Ethyl 10 benzyloxy-7 -ch1oro 11-meth0xy-1,3,12-

sponding acyl malonic ester and cyciizing said ester withtrioxo-1,2,3,4,4a ,5,12,IZa-octahydronaphthacene 2 carsodium hydride toform the corresponding 1,3,12-trioxo- 5 boxylate, 1,2,3,4,4a,5,12,12aoctahydronaphthacene-Z-carboxylate.

a b Y-5- -%I Y -L References Cited in the file of this patent2,3,4,4a,9,9a,10-octahy roan acene.

6. Ethyl 8-benzyloxy-S-chloro-1,2,3,4,4a,9,9a,10-0cta- UNITED STATESPATENTS hydro-1,3,9-trioxo-2-anthroate. 10 2,744,931 Broschard et a1 May8, 1956 7. Ethyl S-chloro-l,2,3,4,4a,9,9a,10-octahydro- 8-hy- 2,783,261Conover Feb. 26, 1957 droxy-1,3,9-trioxo-2-anthroate.

s. S-chloro-S-methoxy-1,3,9-tri0x0 1,2,3,4,4a,9,9a, OTHER REFERENCESlO-octahydroanthracene. Richter: Textbook of Organic Chemistry, pages196 9. 2-carboxainido-5-ch10ro-8-methoxy 1,3,9 triOXO- 15 and 442, I.Wiley (1952).

1,2,3,4,4a,9,9a,10-octahydmanthracene. Muxfeldt et a1.: Chem. Abst., 53,16088 (1959).

I UNITED STATES PATENT OFFICE CERTIFICATIONIOF CORRECTION Iatent No.3,002,993 October 3, 1961 Raymond G, Wilki son et a1.

- It is hereby certified that error appears in the above numbered pat- 5ent requiring correction and that the said Letters Patent should read ascorrected below.

Column 10', lines 33 to 39, the formula should appear as shown belowinstead of as in the patent:

same column 10, lines 16 to 52 the formula should appear as shown belowinstead of as in the patent:

same column l0 lines 65 'to. 7 2, the fi'ormula should appear as shownbelow instead of as in the patient:

Signed and sealed this 3rd day of April W62,

(SEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD Attesting Officer Commissioner of Patents

1. A COMPOUND OF THE FORMULA:
 2. A COMPOUND OF THE FORMULA:
 3. THEMETHOD OF PREPARING A COMPOUND OF THE FORMULA: